The structure of the eye can be divided into two segments: the anterior and posterior. The anterior segment comprises the front third of the eye and includes the structures in front of the vitreous humor: the cornea, iris, ciliary body, and lens. The posterior segment includes the back two-thirds of the eye and includes the sclera, choroid, retinal pigment epithelium, neural retina, optic nerve, and vitreous humor.
Important diseases affecting the anterior segment of the eye include glaucoma, allergic conjunctivitis, anterior uveitis, and cataracts. Diseases affecting the posterior segment of the eye include dry and wet age-related macular degeneration (AMD), cytomegalovirus (CMV) infection, diabetic retinopathy, choroidal neovascularization, acute macular neuroretinopathy, macular edema (such as cystoid macular edema and diabetic macular edema), Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy), retinal arterial occlusive disease, central retinal vein occlusion, uveitic retinal disease, retinal detachment, ocular trauma, damage caused by ocular laser treatment or photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction and retinitis pigmentosa. Glaucoma is sometimes also considered a posterior ocular condition because a therapeutic goal of glaucoma treatment is to prevent or reduce the loss of vision due to damage or loss of retinal cells or optic nerve cells.
Typical routes of drug administration to the eye include topical, systemic, intravitreal, intraocular, intracameral, subconjunctival, subtenon, retrobulbar, and posterior juxtascleral. (Gaudana, R., et al., “Ocular Drug Delivery”, The American Association of Pharmaceutical Scientist Journal, 12(3)348-360, 2010).
A number of types of delivery systems have been developed to deliver therapeutic agents to the eye. Such delivery systems include conventional (solution, suspension, emulsion, ointment, inserts, and gels), vesicular (liposomes, niosomes, discomes, and pharmacosomes), advanced materials (scleral plugs, gene delivery, siRNA, and stem cells), and controlled-release systems (implants, hydrogels, dendrimers, iontophoresis, collagen shields, polymeric solutions, therapeutic contact lenses, cyclodextrin carriers, microneedles, microemulsions, and particulates (microparticles and nanoparticles)).
Treatment of posterior segment diseases remains a daunting challenge for formulation scientists. Drug delivery to the posterior segment of the eye is typically achieved via an intravitreal injection, the periocular route, implant, or by systemic administration. Drug delivery to the posterior segment by way of the periocular route can involve the application of a drug solution to the close proximity of the sclera, which results in high retinal and vitreal concentrations.
Intravitreal injection is often carried out with a 30 gauge or less needle. While intravitreal injections offer high concentrations of drug to the vitreous chamber and retina, they can be associated with various short term complications such as retinal detachment, endophthalmitis and intravitreal hemorrhages. Experience shows that injection of small particles can lead to the rapid dispersal of the particles which can obstruct vision (experienced by the patient as “floaties” or “floaters”) and the rapid removal of the particles from the injection site (which can occur via the lymphatic drainage system or by phagocytosis). In addition, immunogenicity can occur upon recognition of the microspheres by macrophages and other cells and mediators of the immune system.
Complications in periocular injections include rises in intraocular pressure, cataract, hyphema, strabismus, and corneal decompensation. Transscleral delivery with periocular administration is seen as an alternative to intravitreal injections. However, ocular barriers such as the sclera, choroid, retinal pigment epithelium, lymphatic flow, and general blood flow can compromise efficacy. Systemic administration, which is not advantageous given the ratio of the volume of the eye to the entire body, can lead to potential systemic toxicity.
A number of companies have developed microparticles for treatment of eye disorders. For example, Allergan has disclosed a biodegradable microsphere to deliver a therapeutic agent that is formulated in a high viscosity carrier suitable for intraocular injection or to treat a non-ocular disorder (U.S. publication 2010/0074957 and U.S. publication 2015/0147406 claiming priority to a series of applications back to Dec. 16, 2003). In one embodiment, the '957 application describes a biocompatible, intraocular drug delivery system that includes a plurality of biodegradable microspheres, a therapeutic agent, and a viscous carrier, wherein the carrier has a viscosity of at least about 10 cps at a shear rate of 0.1/second at 25° C.
Allergan has also disclosed a composite drug delivery material that can be injected into the eye of a patient that includes a plurality of microparticles dispersed in a media, wherein the microparticles contain a drug and a biodegradable or bioerodible coating and the media includes the drug dispersed in a depot-forming material, wherein the media composition may gel or solidify on injection into the eye (WO 2013/112434 A1, claiming priority to Jan. 23, 2012). Allergan states that this invention can be used to provide a depot means to implant a solid sustained drug delivery system into the eye without an incision. In general, the depot on injection transforms to a material that has a viscosity that may be difficult or impossible to administer by injection.
In addition, Allergan has disclosed biodegradable microspheres between 40 and 200 μm in diameter, with a mean diameter between 60 and 150 μm that are effectively retained in the anterior chamber of the eye without producing hyperemia (US 2014/0294986). The microspheres contain a drug effective for an ocular condition with greater than seven day release following administration to the anterior chamber of the eye. The administration of these large particles is intended to overcome the disadvantages of injecting 1-30 μm particles which are generally poorly tolerated.
Regentec Limited has filed a series of patent applications on the preparation of porous particles that can be used as tissue scaffolding (WO 2004/084968 and U.S. publication 2006/0263335 (filed Mar. 27, 2003) and U.S. publication 2008/0241248 (filed Sep. 20, 2005) and WO 2008/041001 (filed Oct. 7, 2006)). The porosity of the particles must be sufficient to receive cells to be held in the particle. The cells can be added to the matrix at, or prior to, implantation of the matrix or afterward in the case of recruitment from endogenous cells in situ. Regentec also published an article on tissue scaffolding with porous particles (Qutachi et al. “Injectable and porous PLGA microspheres that form highly porous scaffolds at body temperature”, Acta Biomaterialia, 10, 5080-5098, (2014)).
In addition, Regentec Limited also filed patent applications on the preparation of large porous particles that can be used in drug delivery (WO 2010/100506 and U.S. publication 2012/0063997 (filed Mar. 5, 2009)). The porosity of the particles allows for quick delivery of the therapeutic agent. The particles are intended to form a scaffold that fills the space in which they are injected by a trigger such as a change in temperature.
Additional references pertaining to highly porous microparticles include publications by Rahman and Kim. Rahman et al. “PLGA/PEG-hydrogel composite scaffolds with controllable mechanical properties” J. of Biomedical Materials Research, 101, 648-655, (2013) describes hydrogels of approximately 50 percent porosity and their corresponding mechanical properties. Kim et al. “Biodegradable polymeric microspheres with “open/closed” pores for sustained release of human growth hormone” J. of Controlled Release, 112, 167-174, (2006) describes PLGA polymers with pores for the delivery of human growth hormone.
EP 2125048 filed by Locate Therapeutics Limited (filed Feb. 1, 2007) as well as WO 2008/093094, U.S. publication 2010/0063175 (filed Feb. 1, 2007), and WO 2008/093095 (filed Feb. 1, 2007) filed by Regentec Limited disclose the preparation of particles that are not necessarily porous but that when exposed to a trigger (such as temperature) form a tissue scaffold useful in the repair of damaged or missing tissue in a host.
U.S. Pat. No. 9,161,903 issued on Oct. 20, 2015 to Warsaw Orthopedic and U.S. publication 2016/0038407 filed by Warsaw Orthopedic Inc. disclose a flowable composition for injection at a target tissue site beneath the skin that includes a flowable composition that hardens at or near the target tissue site.
Bible et al. “Attachment of stem cells to scaffold particles for intra-cerebral transplantation”, Nat. Protoc., 10, 1440-1453, (2009) describes a detailed process to make microparticles of PLGA that do not clump or aggregate.
U.S. Patent Application Publication 2011/0123446 filed by Liquidia Technologies titled “Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates” describes degradable polymers that utilize a silyl core and can form rapidly degrading matrixes.
Additional references pertaining to particles for ocular delivery include the following. Ayalasomayajula, S. P. and Kompella, U. B. have disclosed the subconjunctival administration of celecoxib-poly(lactide co-glycolide) (PLGA) microparticles in rats (Ayalasomayajula, S. P. and Kompella, U. B., “Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model”, Eur. J. Pharm., 511, 191-198 (2005)). Danbiosyst UK Ltd., has disclosed a microparticle comprising a mixture of a biodegradable polymer, a water soluble polymer of 8,000 Daltons or higher and an active agent (U.S. Pat. No. 5,869,103). Poly-Med, Inc. has disclosed compositions comprising a hydrogel mass and a carrier having a biological active agent deposited on the carrier (U.S. Pat. No. 6,413,539). MacroMed Inc. has disclosed the use of an agent delivery system comprising a microparticle and a biodegradable gel (U.S. Pat. Nos. 6,287,588 and 6,589,549). Novartis has disclosed ophthalmic depot formulations for periocular or subconjunctival administration where the pharmacologically acceptable polymer is a polylactide-co-glycolide ester of a polyol (U.S. publication 2004/0234611, U.S. publication 2008/0305172, U.S. publication 2012/0269894, and U.S. publication 2013/0122064). The Universidad De Navarra has disclosed oral pegylated nanoparticles for carrying biologically active molecules comprising a pegylated biodegradable polymer (U.S. Pat. No. 8,628,801). Surmodics, Inc. has disclosed microparticles containing matrices for drug delivery (U.S. Pat. No. 8,663,674). Minu, L.L.C., has disclosed the use of an agent in microparticle of nanoparticle form to facilitate transmembrane transport. Emory University and Georgia Tech Research Corporation have disclosed particles dispersed in a non-Newtonian fluid that facilitates the migration of the therapeutic particles from the insertion site in the suprachoroidal space to the treatment site (U.S. 2016/0310417). Pfizer has disclosed nanoparticles as injectable depot formulations (U.S. publication 2008/0166411). Abbott has disclosed a pharmaceutical dosage form that comprises a pharmaceutically acceptable polymer for the delivery of a tyrosine kinase inhibitor (U.S. publication 2009/0203709). The Brigham and Woman's Hospital, Inc. has disclosed modified poly(lactic-co-glycolic) polymers having therapeutic agents covalently bound to the polymer (U.S. 2012/0052041). BIND Therapeutics, Inc. has disclosed therapeutic nanoparticles comprising about 50 to 99.75 weight percent of a diblock poly (lactic) acid-poly(ethylene)glycol copolymer or a diblock poly (lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer wherein the therapeutic nanoparticle comprises 10 to about 30 weight percent poly(ethylene)glycol (U.S. publication 2014/0178475). Additional publications assigned to BIND Therapeutics, Inc. include U.S. publication 2014/0248358 and U.S. publication 2014/0249158. Allergan has disclosed the use of biodegradable microspheres containing a drug to treat an ocular condition (U.S. publication 2010/0074957, U.S. publication 2014/0294986, U.S. publication 2015/0147406, EP 1742610, and WO 2013/112434). Allergan has also disclosed a biocompatible implant containing a prostamide component, which can exist in particle form, and a biodegradable polymer that allows for slow release of the drug over the course of 1 week to 6 months for the treatment of an ocular condition, such as glaucoma (U.S. application 2015/0157562 and U.S. application 2015/0099805). Jade Therapeutics has disclosed formulations containing an active agent and a polymer matrix that can be delivered directly to the target tissue or placed in a suitable delivery device (U.S. publication 2014/0107025). Bayer Healthcare has disclosed a topical ophthalmological pharmaceutical composition comprising sunitinib and at least one pharmaceutically acceptable vehicle (WO 2013/188283). pSivida Us, Inc. has disclosed biodegradable drug eluting particles comprising a microporous or mesoporous silicon body for intraocular use (U.S. Pat. No. 9,023,896). Additional patents assigned to pSivida Us, Inc. include: U.S. Pat. Nos. 8,871,241; 8,815,284; 8,574,659; 8,574,613; 8,252,307; 8,192,408 and 7,998,108. ForSight Vision4, Inc. has disclosed therapeutic devices for implantation in the eye (U.S. Pat. No. 8,808,727). Additional patents assigned to ForSight Vision4, Inc. include: U.S. Pat. Nos. 9,125,735; 9,107,748; 9,066,779; 9,050,765; 9,033,911; 8,939,948; 9,905,963; 8,795,712; 8,715,346; 8,623,395; 8,414,646; 8,399,006; 8,298,578; 8,277,830; 8,167,941; 7,883,520; 7,828,844 and 7,585,075. The Nagoya Industrial Science Research Institute has recently disclosed the use to liposomes to deliver a drug to the posterior segment of the eye (U.S. Pat. No. 9,114,070).
In order to treat ocular diseases, and in particular diseases of the posterior segment, the drug must be delivered in therapeutic levels and for a sufficient duration to achieve efficacy. This seemingly straightforward goal is difficult to achieve in practice.
The object of this invention is to provide compositions and methods to treat ocular disorders. Another objective is to provide drug delivering microparticles for sustained administration of therapeutic materials generally in vivo.